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Insulin-like growth factor (IGF-1) is essential for cellular metabolism and proliferation. Elevated dietary protein results in increased renal IGF-1 synthesis with corresponding decrease in IGF binding protein 1 (IGF BP-1) in medullary thick ascending limb (MTAL) epithelial cells. The local autocrine or paracrine action of IGF-1 results in proliferation of MTAL epithelial cells.

The role of insulin-like growth factor I (IGF-I) in myelin regeneration was studied using cuprizone to produce demyelinating lesions in the brain areas of cuprizone-fed mice. The levels of IGF-I and its receptors were then examined atboth genetic and peptide levels. The results showed that IGF-I expression was induced in astrocytes located at the demyelinated lesions. This expression decreased during recovery. Furthermore, there was also an increase in oligodendroglial IGF-I receptor expression during early recovery. The results suggest that IGF-I functions as a diffusible element that stimulates oligodendroglial-mediated activity towards myelin regeneration.

Abstract Background A number of neurodevelopmental syndromes are caused by mutations in genes encoding proteins that normally function in epigenetic regulation. Identification of epigenetic alterations occurring in these disorders could shed light on molecular pathways relevant to neurodevelopment. Results Using a genome-wide approach, we identified genes with significant loss of DNA methylation in blood of males with intellectual disability and mutations in the X-linked KDM5C gene, encoding a histone H3 lysine 4 demethylase, in comparison to age/sex matched controls. Loss of DNA methylation in such individuals is consistent with known interactions between DNA methylation and H3 lysine 4 methylation. Further, loss of DNA methylation at the promoters of the three top candidate genes FBXL5, SCMH1, CACYBP was not observed in more than 900 population controls. We also found that DNA methylation at these three genes in blood correlated with dosage of KDM5C and its Y-linked homologue KDM5D. In addition, parallel sex-specific DNA methylation profiles in brain samples from control males and females were observed at FBXL5 and CACYBP. Conclusions We have, for the first time, identified epigenetic alterations in patient samples carrying a mutation in a gene involved in the regulation of histone modifications. These data support the concept that DNA methylation and H3 lysine 4 methylation are functionally interdependent. The data provide new insights into the molecular pathogenesis of intellectual disability. Further, our data suggest that some DNA methylation marks identified in blood can serve as biomarkers of epigenetic status in the brain.

The brain has enormous anabolic needs during early postnatal development. This study presents multiple lines of evidence showing that endogenous brain insulin-like growth factor 1 (Igf1) serves an essential, insulin-like role in promoting neuronal glucose utilization and growth during this period. Brain 2-deoxy-D- [1-[sup.14]C]glucose uptake parallels Igf1 expression in wild-type mice and is profoundly reduced in Igf1-/- mice, particularly in those structures where Igf1 is normally most highly expressed. 2-Deoxy-D-[1-[sup.14]C]glucose is significantly reduced in synaptosomes prepared from Igf1-/- brains, and the deficit is corrected by inclusion of Igf1 in the incubation medium. The serine/threonine kinase Akt/ PKB is a major target of insulin-signaling in the regulation of glucose transport via the facilitative glucose transporter (GLUT4) and glycogen synthesis in peripheral tissues. Phosphorylation of Akt and GLUT4 expression are reduced in Igf1-/- neurons. Phosphorylation of glycogen synthase kinase 3[Beta] and glycogen accumulation also are reduced in Igf1-/- neurons. These data support the hypothesis that endogenous brain Igf1 serves an anabolic, insulin-like role in developing brain metabolism. mental retardation | glycogen synthase kinase | glucose transporter | GLUT4 | Akt